title: Activated Cdc42-associated kinase 1 (Ack1) is required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor recruitment to lipid rafts and induction of cell death.
abstract: TNF-related apoptosis-inducing ligand (TRAIL) holds promise for treatment of cancer due to its ability to selectively kill cancer cells while sparing normal cells. Ligand-induced translocation of TRAIL receptors (TRAIL-R) 1 and 2 (also called DR4 and DR5, respectively) into lipid raft membrane microdomains is required for TRAIL-induced cell death by facilitating receptor clustering and formation of the death-inducing signaling complex, yet the underlying regulatory mechanisms remain largely unknown. We show here that the non-receptor tyrosine kinase Ack1, previously implicated in the spatiotemporal regulation of the EGF receptor, is required for TRAIL-induced cell death in multiple epithelial cell lines. TRAIL triggered a transient up-regulation of Ack1 and its recruitment to lipid rafts along with TRAIL-R1/2. siRNA-mediated depletion of Ack1 disrupted TRAIL-induced accumulation of TRAIL-R1/2 in lipid rafts and efficient recruitment of caspase-8 to the death-inducing signaling complex. Pharmacological inhibition of Ack1 did not affect TRAIL-induced cell death, indicating that Ack1 acts in a kinase-independent manner to promote TRAIL-R1/2 accumulation in lipid rafts. These findings identify Ack1 as an essential player in the spatial regulation of TRAIL-R1/2.
authors.affiliation: From the Wolfson Institute for Biomedical Research, University College London, WC1E 6BT London, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Linderoth
authors.forename: Giulia
authors.initials: G
authors.lastname: Pilia
authors.forename: Nupam P
authors.initials: NP
authors.lastname: Mahajan
authors.forename: Ingvar
authors.initials: I
authors.lastname: Ferby
mesh_terms: D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: Apoptosis; Cancer; Cell Signaling; Lipid Rafts; TRAIL; Tyrosine-Protein Kinase (Tyrosine Kinase)